{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:11:39Z","timestamp":1791209499551,"version":"4.1.0"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2006,3,7]],"date-time":"2006-03-07T00:00:00Z","timestamp":1141689600000},"content-version":"vor","delay-in-days":6,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2006,3]]},"abstract":"<jats:p>Na<jats:sup>+<\/jats:sup>\u2013Ca<jats:sup>2+<\/jats:sup> exchange (NCX) current has been suggested to play a role in cardiac pacemaking, particularly in association with Ca<jats:sup>2+<\/jats:sup> release from the sarcoplasmic reticulum (SR) that occurs just before the action potential upstroke. The present experiments explore in more detail the contribution of NCX to pacemaking. Na<jats:sup>+<\/jats:sup>\u2013Ca<jats:sup>2+<\/jats:sup> exchange current was inhibited by rapid switch to low\u2010Na<jats:sup>+<\/jats:sup> solution (with Li<jats:sup>+<\/jats:sup> replacing Na<jats:sup>+<\/jats:sup>) within the time course of a single cardiac cycle to avoid slow secondary effects. Rapid switch to low\u2010Na<jats:sup>+<\/jats:sup> solution caused immediate cessation of spontaneous action potentials. ZD7288 (3 \u03bc<jats:sc>m<\/jats:sc>), to block <jats:italic>I<\/jats:italic><jats:sub>f<\/jats:sub> (funny current) channels, slowed but did not stop the spontaneous activity, and tetrodotoxin (10 \u03bc<jats:sc>m<\/jats:sc>), to block Na<jats:sup>+<\/jats:sup> channels, had little effect, but in the presence of either of these agents, rapid switch to low\u2010Na<jats:sup>+<\/jats:sup> solution again caused immediate cessation of spontaneous action potentials. Spontaneous electrical activity was also stopped following loading of the cells with the Ca<jats:sup>2+<\/jats:sup> chelators BAPTA and EGTA, and by exposure to the NCX inhibitor KB\u2010R7943 (5 \u03bc<jats:sc>m<\/jats:sc>). When rapid switch to low\u2010Na<jats:sup>+<\/jats:sup> solution caused cessation of spontaneous activity, this was found (using confocal microscopy, with fluo\u20104 as the Ca<jats:sup>2+<\/jats:sup> probe) to be accompanied by an initial fall in cytosolic [Ca<jats:sup>2+<\/jats:sup>], with subsequent appearance of Ca<jats:sup>2+<\/jats:sup> waves. Inhibition of SR Ca<jats:sup>2+<\/jats:sup> uptake with cyclopiazonic acid (CPA, 30 \u03bc<jats:sc>m<\/jats:sc>) slowed but did not stop spontaneous activity. Rapid switch to low\u2010Na<jats:sup>+<\/jats:sup> solution in the presence of CPA caused abolition of spontaneous Ca<jats:sup>2+<\/jats:sup> transients and a progressive rise in cytosolic [Ca<jats:sup>2+<\/jats:sup>]. With ratiometric fluorescence methods (indo\u20105F as the Ca<jats:sup>2+<\/jats:sup> probe), the minimum level of [Ca<jats:sup>2+<\/jats:sup>] between beats was found to be approximately 225 n<jats:sc>m<\/jats:sc>, and abolition of beating with nifedipine, acetylcholine or adenosine caused a fall in cytosolic [Ca<jats:sup>2+<\/jats:sup>] below this level. These observations support the hypothesis that NCX current is essential for normal pacemaker activity under the conditions of our experiments. A continuous depolarizing influence of current through the NCX protein might result from maintained electrogenic NCX (with 3:1 stoichiometry, supported by a cytosolic [Ca<jats:sup>2+<\/jats:sup>] that normally does not fall below 225 n<jats:sc>m<\/jats:sc> between beats) and\/or from a novel, recently suggested role of the NCX protein to allow a Na<jats:sup>+<\/jats:sup> leak pathway.<\/jats:p>","DOI":"10.1113\/jphysiol.2005.100305","type":"journal-article","created":{"date-parts":[[2006,1,20]],"date-time":"2006-01-20T01:23:25Z","timestamp":1137720205000},"page":"639-649","source":"Crossref","is-referenced-by-count":102,"title":["Fundamental importance of Na<sup>+<\/sup>\u2013Ca<sup>2+<\/sup> exchange for the pacemaking mechanism in guinea\u2010pig sino\u2010atrial node"],"prefix":"10.1113","volume":"571","author":[{"given":"Luke","family":"Sanders","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stevan","family":"Rakovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Lowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul A. 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